IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지

A Current Research Insight into Function and Development of Adjuvants

면역보조제의 작용 및 개발

  • Sohn, Eun-Soo (Department of Information Analysis, Korea Institute of Science and Technology Information (KISTI)) ;
  • Son, EunWha (Department of Pharmacognosy Material Development, Samcheok National University) ;
  • Pyo, SuhkNeung (Division of Immunopharmacology, College of Pharmacy, Sungkyunkwan University)
  • 손은수 (한국과학기술정보연구원(KISTI) 정보분석부) ;
  • 손은화 (삼척국립대학교 생약자원개발학과) ;
  • 표석능 (성균관대학교 약학부)
  • Published : 2004.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

In recent years, adjuvants have received much attention because of the development of purified subunit and synthetic vaccines which are poor immunogens and require adjuvants to evoke the immune response. Therefore, immunologic adjuvants have been developed and testing for most of this century. During the last years much progress has been made on development, isolation and chemical synthesis of alternative adjuvants such as derivatives of muramyl dipeptide, monophosphoryl lipid A, liposomes, QS-21, MF-59 and immunostimulating complexes (ISCOMS). Biodegradable polymer microspheres are being evaluated for targeting antigens on mucosal surfaces and for controlled release of vaccines with an aim to reduce the number of doses required for primary immunization. The most common adjuvants for human use today are aluminum hydroxide and aluminum phosphate. Calcium phosphate and oil emulsions have been also used in human vaccination. The biggest issue with the use of adjuvants for human vaccines is the toxicity and adverse side effects of most of the adjuvant formulations. Other problems with the development of adjuvants include restricted adjuvanticity of certain formulations to a few antigens, use of aluminum adjuvants as reference adjuvant preparations under suboptimal conditions, non-availability of reliable animal models, use of non-standard assays and biological differences between animal models and humans leading to the failure of promising formulations to show adjuvanticity in clinical trials. The availability of hundreds of different adjuvants has prompted a need for identifying rational standards for selection of adjuvant formulations based on safety and sound immunological principles for human vaccines. The aim of the present review is to put the recent findings into a broader perspective to facilitate the application of these adjuvants in general and experimental vaccinology.

Keywords

References

  1. Ramon, G: Sur l'augmentation anormale de l'antitoxine chez les cheveux producteurs de serum antidiphterique. Bulletin de Societe Centrale de Medicine Veterinaire 101;227-234, 1925
  2. Ramon G: Procedres pour acroitre la production des antitoxines. Ann Inst Pasteur 40;1-10, 1926
  3. Glenny AT, Pope CG, Waddington H, Wallace V: The antigenic value of toxoid precipitated by potassium alum. J Path Bact 29;38-45, 1926
  4. Freund J, Casals J, Hosmer EP: Sensitization and antibody formation bacilli and parafin oil. Proc Soc Exp Biol Med 37;509-513, 1937 https://doi.org/10.3181/00379727-37-9625
  5. Johnson AG, Gaines S, Landy M: Studies on the O antigen of Salmonella typhosa V. Enhancement of antibody response to protein antigens by the purified lipopolysaccharide. J Exp Med 103;225-246, 1956 https://doi.org/10.1084/jem.103.2.225
  6. Ellouz F, Adam A, Ciorbaru R, Lederer E: Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives. Biochem Biophys Res Commun 59;1317-1325, 1974 https://doi.org/10.1016/0006-291X(74)90458-6
  7. Masek K, Zaoral M, Jezek J, Straka R: Immunoadjuvant activity of synthetic N-acetyl muramyl dipeptide. Experientia 34;1363-1364, 1978 https://doi.org/10.1007/BF01981474
  8. Newman MJ, Wu YJ, Gardner BH, Munroe KJ, Leombruno D, Recchai J, Kensil CR, Coughlin RT: Saponin adjuvant induction of ovalbumin-specific CD8+ cytotoxic T lymphocyte responses. J Immunol 148;2357-2362, 1992
  9. Vogel FR, Powell MF: A summary compendium of vaccine adjuvants and excipients. In: Powell MF, Newman MJ eds.: Vacine design: The subunit and adjuvant approach, New York, Plenum Publishing Corp., 1995
  10. Allison AC, Byars NE: Immunological adjuvants: Desirable properties and side-effects. Molecular Immunology 28;279-284, 1991 https://doi.org/10.1016/0161-5890(91)90074-T
  11. Alving CR: Design and selection of vaccine adjuvants: animal models and human trials. Vaccine 20 Supplement 3;S56-S64, 2002 https://doi.org/10.1016/S0264-410X(02)00174-3
  12. Gupta RK, Siber GR: Adjuvants for human vaccines-current status, problems and future prospects. Vaccine 13;1263-1276, 1995. https://doi.org/10.1016/0264-410X(95)00011-O
  13. Wu JY, Gardner BH, Kushner NN, Pozzi LA, Kensil CR, Cloutier PA, Coughlin RT, Newman MJ: Accessory cell requirements for saponin adjuvant-induced class I MHC antigen-restricted cytotoxic T-lymphocytes. Cell Immunol 154; 393-406, 1994. https://doi.org/10.1006/cimm.1994.1086
  14. Kovacsovics-Bankowski M, Rock KL: Presentation of exogenous antigens by macrophages: analysis of major histocompatibility complex class I and II presentation and regulation by cytokines. Eur J Immunol 24;2421-2428, 1994 https://doi.org/10.1002/eji.1830241024
  15. Relyveld EH: Detoxification of microbial toxins with glutaraldehyde and their use in the preparation of vaccines. In: Rosenberg P eds.: Toxins: Animal, Plant and Microbial, p1049-1065, Oxford, Pergamon Press, 1978
  16. Relyveld EH, Ben-Efraim S: Preparation of vaccines by the action of glutaraldehyde on toxins, bacteria, viruses, allergens and cells. In: Langone JJ, van Vunakis H eds.: Methods in Enzymology, p24-60, New York, Academic Press, 1983
  17. Michael JG, Pesce AJ, Flanagan M: Enhanced immunogenicity of cationized proteins. In: Spriggs DR, Koff WC eds.: Topics in Vaccine Adjuvant Research, p99-107, Boca Raton, CRC Press, 1991
  18. Herrington DA, Clyde DF, Losonsky G, Cortesia M, Murphy JR, Davis J, Baqar S, Felix AM, Heimer EP, Gillessen D, et al: Safety and immunogenicity in man of a synthetic peptide malaria vaccine against Plasmodium falciparum sporozoites. Nature. 16-22;257-259, 1987
  19. Nash H, Talwar GP, Segal SJ, et al: Obsenrations on the antigenicity and clinical effects of a candidate anti-pregnancy vaccine: beta subunit of human chorionic gonadotropin linked to tetanus toxoid. Fertil Steril 34;328-335, 1980 https://doi.org/10.1016/S0015-0282(16)45019-3
  20. Robbins JB, Schneerson R: Polysaccharide-protein conjugates: a new generation of vaccines. J Infect Dis 161;821-832, 1990 https://doi.org/10.1093/infdis/161.5.821
  21. Crook SJ, Stewart R, Boggs JM, Vistnes AI, Zalc B: Characterization of anti-cerebroside sulfate antisera using a theoretical model to analyse liposome immune lysis data. Mol Immunol 24;1135-1143, 1987 https://doi.org/10.1016/0161-5890(87)90159-3
  22. Linuma H, Nerome K, Yoshioka Y, Okinaga K: Characteristics of cytotoxic T-lymphocytes directed to influenza virus haemagglutinin elicited by immunisation with muramyl dipeptide-influenza liposome vaccine. Stand J lmmunol 41;1-10, 1995 https://doi.org/10.1111/j.1365-3083.1995.tb03526.x
  23. Pardoll DM: Paracrine cytokine adjuvants in cancer immunotherapy. Annu Rev Immunol 13;399-415, 1995 https://doi.org/10.1146/annurev.iy.13.040195.002151
  24. Heath AW, Playfair JHL: Cytokines as immunological adjuvants. Vaccine 10;427-434, 1992 https://doi.org/10.1016/0264-410X(92)90389-2
  25. Edelman R: Vaccine adjuvants. Rev infect Dis 2;370-383, 1980 https://doi.org/10.1093/clinids/2.3.370
  26. Hunter RL: Overview of vaccine adjuvants: present and future. Vaccine 20;S7-S12, 2002 https://doi.org/10.1016/S0264-410X(02)00164-0
  27. Takahashi H, Takashita T, Morein B, Putney S, Germain RN, Berzofsky JA: Induction of CD8+ cytotoxic cells by immunization with purified HIV-1 envelope protein in ISCOMs. Nature 344;873-875, 1990 https://doi.org/10.1038/344873a0
  28. Grun JL, Maurer PH: Different T helper cell subsets elicited in mice utilizing two different adjuvant vehicles: the role of endogenous interleukin 1 in proliferative responses. Cell Immunol 121;134-145, 1989 https://doi.org/10.1016/0008-8749(89)90011-7
  29. Xu-Amano J, Kiyono H, Jackson RJ, Staats HF, Fujihashi K, Burrows PD, Elson CO, Pillai S, McGhee JR: Helper T cell subsets for immunoglobulin A responses: oral immunization with tetanus toxoid and cholera toxin as adjuvant selectively induces Th2 cells in mucosa associated tissues. J Exp Med 178;1309-1320, 1993 https://doi.org/10.1084/jem.178.4.1309
  30. Allison AC: The mode of action of immunological adjuvants. Dev Biol Stand 92;3-11, 1998
  31. Phillips NC, Emili A: Enhanced antibody responses to liposome-associated protein antigens: preferential stimulation of IgG2a/b production. Vaccine 10;151-158, 1992 https://doi.org/10.1016/0264-410X(92)90004-4
  32. Bliss J, Van Cleave V, Murray K, Wiencis A, Ketchum M, Maylor R, Haire T, Resmini C, Abbas AK, Wolf SF: IL-12, as an adjuvant, promotes a T helper 1 cell, but does not suppress a T helper 2 cell recall response. J Immunol 156;887-894, 1996
  33. McGhee JR: Helper T cell subsets for immunoglobulin A responses: oral immunization with tetanus toxoid and cholera toxin as adjuvant selectively induces Th2 cells in mucosa associated tissues. J Exp Med 178;1309-1320, 1993 https://doi.org/10.1084/jem.178.4.1309
  34. Brown WC, Woods VM, Chitko-McKown CG, Hash SM, Rice-Ficht AC: Interleukin-10 is expressed by bovine type 1 helper, type 2 helper, and unrestricted parasite-specific T-cell clones and inhibits proliferation of all three subsets in an accessory-cell-dependent manner. Infect Immun 62;4697-4708, 1994
  35. Gupta RK: Aluminum compounds as vaccine adjuvants. Adv Drug Deliv Rev 32;155-172, 1998 https://doi.org/10.1016/S0169-409X(98)00008-8
  36. C'Hagan DT, Jeffet-y H, Davis SS: Long-term antibody responses in mice following subcutaneous immunization with ovalbumin entrapped in biodegradable microparticles. Vaccine 11;965-969, 1993 https://doi.org/10.1016/0264-410X(93)90387-D
  37. Sjolander A, Drane D, Maraskovsky E, Scheerlinck J, Suhrbier A, Tennent J, Pearse M: Immune responses to ISCOMw formulations in animal and primate models. Vaccine 19;2661-2665, 2001. https://doi.org/10.1016/S0264-410X(00)00497-7
  38. Siber GR, Anderson R, Habafy M, Gupta RK: Development of a guinea-pig model to assess immunogenicity of Haemophilus influenzae type b capsular polysaccharide conjugate vaccines. Vaccine 13;525-531, 1995 https://doi.org/10.1016/0264-410X(94)00042-L
  39. Gupta RK, Anderson R, Cecchini D, Rost B, Griffin P Jr, Benscoter K, Xu J, Montanez-Ortiz L, Siber GR: Development of a guinea-pig model for potency/ immunogenicity evaluation of diphtheria, tetanus acellular pertussis (DTaP) and Haemophilus influenzae type b polysaccharide conjugate vaccines. Dev Biol Stand 86;283-296, 1996
  40. Glenny AT, Buttle GAH, Stevens MF: Rate of disappearance of diphtheria toxoid injected into rabbits and guinea-pigs: toxoid precipitated with alum. J Pathol 34;267-275, 1931. https://doi.org/10.1002/path.1700340214
  41. Maschmann E, Kuster E, Fischer W: Uber die Fahigkeit des Tonerde-Praparates B, Diphtherie-Toxin zu adsorbieren. Ber Dtsch Chem Ges 64;2174-2178, 1931 https://doi.org/10.1002/cber.19310640851
  42. Ericsson H; Purification and adsorption of diphtheria toxoid. Nature 158;350-351, 1946. https://doi.org/10.1038/158350a0
  43. Mancino D, Ovary Z: Adjuvant effects of amorphous silica and of aluminium hydroxide on IgE and IgGl antibody production in different inbred mouse strains. Int Arch Allergy Appl Immun 61;253-258, 1980 https://doi.org/10.1159/000232443
  44. Barr IG, Sjolander A, Cox JC: ISCOMs and other saponin based adjuvants. Adv Drug Deliv Rev 32;247-271, 1998 https://doi.org/10.1016/S0169-409X(98)00013-1
  45. Claassen E, Boersma WJA: Characteristics and practical use of new-generation adjuvants as an acceptable alternative to Freund's complete adjuvant. Res Immunol 143;475-477, 1992 https://doi.org/10.1016/0923-2494(92)80056-Q
  46. Lewis PA, Loomis D: Allergic irritability. The formation of anti-sheep hemolytic amboceptor in the normal and tuberculous guinea pig. J Exp Med 40;503, 1924 https://doi.org/10.1084/jem.40.4.503
  47. Lefrancier P, Derrien M, Lederman I, Niff F, Choay J, Lederer E: Synthesis of some new analogs of the immunoadjuvant glycopeptide MDP (Nacetyl-muramyl-L-alanyl- Disoglutamine). Int J Pep Prot Res 11;289-296, 1978
  48. Cohen LY, Bahr GM, Darcissac EC, Parant MA: Modulation of expression of class II MHC and CD40 molecules in murine B cells by various muramyl dipeptides. Cell Immunol 169;75-84, 1996 https://doi.org/10.1006/cimm.1996.0093
  49. Johnson AG, Tomai MA: A study of the cellular and molecular mediators of the adjuvant action of a nontoxic monophosphoryl lipid A. Adv Exp Med Biol 256;567-579, 1990
  50. Ulrich JT, Myers KR: Monophosphoryl lipid A as an adjuvant: past experiences and new directions. Pharm Biotechnol 6;495-524, 1995
  51. Dalsgaard K: A study of the isolation and characterization of the saponin quil A. Evaluation of its adjuvant activity, with a special reference to the application in the vaccination of cattle against foot-and-mouth disease. Acta Vet Stand 69;1-40, 1978
  52. Nunberg J, Doyle MV, York SM, York CJ: Interleukin 2 acts as an adjuvant to enhance the potency of inactivated rabies vaccine. Proc Natl Acad Sci USA 86;4240-4243, 1989 https://doi.org/10.1073/pnas.86.11.4240
  53. Odean MJ, Frane CM, Van der Vieren M, Tomai MA, Johnson AG: Involvement of gamma interferon in antibody enhancement by adjuvants. Infect Immun 58;427-432, 1990
  54. Luis C, Afonso C, Scharton TM, Vieira LQ, Wysocka M, Trinchieri G, Scott P: The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science 263;235-237, 1994 https://doi.org/10.1126/science.7904381
  55. Le Moignic, Pinoy: Application to man of vaccines consisting of emulsions in fatty substances (lipo-vaccines). Comp Rend Sot Biol 29;352-358, 1916
  56. Dupuis M, Murphy TJ, Higgins D, Ugozzoli M, Van Nest G, Ott G, McDonald DM: Dendritic cells internalize vaccine adjuvant after intramuscular injection. Cell Immunol 186;18-27, 1998 https://doi.org/10.1006/cimm.1998.1283
  57. Shahum E, Therien HM: Liposomal adjuvanticity: effect of encapsulation and surface-linkage on antibody production and proliferative response. Int J Immunopharmacol 17;9-20, 1995 https://doi.org/10.1016/0192-0561(94)00082-Y
  58. Powers DC, Manning MC, Hanscome PJ, Pietrobon PJF: Cytotoxic T lymphocyte responses to a liposomeadjuvanted influenza A virus vaccine in the elderly. J Infect Dis 172;1103-1107, 1995 https://doi.org/10.1093/infdis/172.4.1103
  59. Gluck R, Mischler R, Brantschen S, Just M, Althaus B, Cryz SJ Jr: lmmunopotentiating reconstituted influenza virus virosome vaccine delivery system for immunization against hepatitis A. J Clin Invest 90;2491-2495, 1992 https://doi.org/10.1172/JCI116141
  60. Gkick R, Mischler R, Finkel B, Que JU, Scarpa B, Cryz SJ Jr: lmmunogenicity of new virosome influenza vaccine in elderly people. Lancet 344;160-163, 1994. https://doi.org/10.1016/S0140-6736(94)92758-8
  61. Liivgren-Bengtsson K, Sjblander A: Adjuvant activity of iscoms; effect of ratio and co-incorporation of antigen and adjuvant. Vaccine 14;753-760, 1996 https://doi.org/10.1016/0264-410X(95)00253-W
  62. Men Y, Gander B, Merkle HP, Corradin G: Induction of sustained and elevated immune responses to weakly immunogenic synthetic malarial peptides by encapsulation in biodegradable polymer microspheres. Vaccine 14;1442-1450, 1996 https://doi.org/10.1016/S0264-410X(96)00074-6
  63. Shahin R, Leef M, Eldridge J, Hudson M, Gilley R: Adjuvanticity and protective immunity elicited by Bordetella pertussis antigens encapsulated in poly (DL-lactide-co- glycolide) microspheres. Infect Immun 63;1195-1200, 1995
  64. Aguado MT, Lambert PH: Controlled-release vaccines- biodegradable polylactide/polyglycolide (PUPG) microspheres as antigen vehicles. lmmunobiology 184;113-125, 1992 https://doi.org/10.1016/S0171-2985(11)80470-5
  65. Cox JC, Coulter AR: Adjuvants-a classification and review of their modes of action. Vaccine 15;248-256, 1997 https://doi.org/10.1016/S0264-410X(96)00183-1
  66. Gupta RK, Siber GR: Comparison of adjuvant activities of aluminum phosphate, calcium phosphate and stearyl tyrosine for tetanus toxoid. Biologicals 22;53-63, 1994 https://doi.org/10.1006/biol.1994.1008
  67. Chu RS, Targoni OS, Krieg AM, Lehmann PV, Harding CV: CpG oligodeoxynucleotides act as adjuvants that switch on T helper 1 (Th1) immunity. J Exp Med 186;1623-1631, 1997 https://doi.org/10.1084/jem.186.10.1623
  68. Schneerson R, Fattom A, Szu SC, Bryla D, Ulrich JT, Rudbach JA, Schiffman G, Robbins JB: Evaluation of monophosphoryl lipid A (MPL) as an adjuvant. Enhancement of the serum antibody response in mice to polysaccharide- protein conjugates by concurrent injection with MPL. J Immunol 147;2136-2140, 1991
  69. Holmgren J, Lycke N, Czerkinsky C: Cholera toxin and cholera B subunit as oral-mucosal adjuvant and antigen vector systems. Vaccine 11;1179-1184, 1993 https://doi.org/10.1016/0264-410X(93)90039-Z
  70. Okahashi N, Yamamoto M, Vancott JL, Chatfield SN, Roberts M, Bluethmann H, Hiroi T, Kiyono H, McGhee JR: Oral immunization of interleukin-4 (IL-4) knockout mice with a recombinant Salmonella strain or cholera toxin reveals that CD4+ Th2 cells producing IL-6 and IL-10 are associated with mucosal immunoglobulin A responses. Infect Immun 64;1516-1525, 1996
  71. Lycke N, Tsuji T, Holmgren J: The adjuvant effect of Vibrio cholerae and Escherichia coli heat-labile enterotoxins is linked to their ADP-ribosyltransferase activity. Eur J Immunol 22;2277-2281, 1992 https://doi.org/10.1002/eji.1830220915
  72. de Haan L, Holtrop M, Verweij WR, Agsteribbe E, Wilschut J: Mucosal immunogenicity of the Escherichia coli heat-labile enterotoxin: role of the A subunit. Vaccine 14;260-266, 1996 https://doi.org/10.1016/0264-410X(95)00235-S
  73. Chong C, Friberg M, Clements JD: LT(R192G), a non-toxic mutant of the heat-labile enterotoxin of Escherichia coli, elicits enhanced humoral and cellular immune responses associated with protection against lethal oral challenge with Salmonella spp. Vaccine 16;732-740, 1998 https://doi.org/10.1016/S0264-410X(97)00255-7
  74. Roberts M, Bacon A, Rappuoli R, Pizza M, Cropley I, Douce G, Dougan G, Marinaro M, McGhee J, Chatfield S: A mutant pertussis toxin molecule that lacks ADP-ribosyltransferase activity, PT-9K/129G, is an effective mucosal adjuvant for intranasally delivered proteins. Infect Immun 63;2100-2108, 1995
  75. Mu HH, Sewell WA: Regulation of DTH and IgE responses by IL-4 and IFN-gamma in immunized mice given pertussis toxin. Immunology 83;639-645, 1994
  76. Ellouz F, Adam A, Ciobaru R, Lederer E: Minimal structural requirements for adjuvant activity of bacterial peptidoglycan derivatives. Biochem Biophys Res Commun 59;1317-1325, 1974 https://doi.org/10.1016/0006-291X(74)90458-6
  77. Lindblad EB, Elhay MJ, Silva R, Appelberg R, Andersen P: Adjuvant modulation of immune responses to tuberculosis subunit vaccines. Infect Immun 65;623-629, 1997
  78. Putkonen P, Nilsson C, Walther L, Ghavamzadeh L, Hild K, Broliden K, Biberfeld G, Thorstensson R: Efficacy of inactivated whole HIV-2 vaccines with various adjuvants in cynomolgus monkeys. J Med Primatol 23;89-94, 1994 https://doi.org/10.1111/j.1600-0684.1994.tb00107.x
  79. Dupuis M, Murphy TJ, Higgins D, Ugozzoli M, Van Nest G, Ott G, McDonald DM: Dendritic cells internalize vaccine adjuvant after intramuscular injection. Cell Immunol 186;18- 27, 1998 https://doi.org/10.1006/cimm.1998.1283
  80. Kahn JO, Sinangil F, Baenziger J, Murcar N, Wynne D, Coleman RL, Steimer KS, Dekker CL, Chernoff D: Clinical and immunologic responses to human immunodeficiency virus (HIV) type 1SF2 gp120 subunit vaccine combined with MF59 adjuvant with or without muramyl tripeptide dipalmitoyl phosphatidylethanolamine in non-HIV-infected human volunteers. J Infect Dis 170;1288-1291, 1994 https://doi.org/10.1093/infdis/170.5.1288
  81. Ott G, Barchfeld GL, Van Nest G: Enhancement of humoral response against human influenza vaccine with the simple submicron oil/water emulsion adjuvant MF59. Vaccine 13;1557-1562, 1995 https://doi.org/10.1016/0264-410X(95)00089-J
  82. Gupta RK, Relyveld EH, Lindblad EB, Bizzini B, Ben-Efraim S, Gupta CK: Adjuvants-a balance between toxicity and adjuvanticity. Vaccine 11;294-306, 1993
  83. Byars NE, Fraser-Smith EB, Pecyk RA, Welch M, Nakano G, Burke RL, Hayward AR, Allison AC: Vaccinating guinea pigs with recombinant glycoprotein D of herpes simplex virus in an efficacious adjuvant formulation elicits protection against vaginal infection. Vaccine 12;200-209, 1994 https://doi.org/10.1016/0264-410X(94)90195-3
  84. Putkonen P, Nilsson C, Walther L, Ghavamzadeh L, Hild K, Broliden K, Biberfeld G, Thorstensson R: Efficacy of inactivated whole HIV-2 vaccines with various adjuvants in cynomolgus monkeys. J Med Primatol 23;89-94, 1994 https://doi.org/10.1111/j.1600-0684.1994.tb00107.x
  85. Sjolander A, van't Land B, Lovgren Bengtsson K: Iscoms containing purified Quillaja saponins upregulate both Th1-like and Th2-like immune responses. Cell Immunol 177;69-76, 1997 https://doi.org/10.1006/cimm.1997.1088
  86. Richards RL, Rao M, Wassef NM, Glenn GM, Rothwell SW, Alving CR: Liposomes containing lipid A serve as an adjuvant for induction of antibody and cytotoxic T-cell responses against RTS,S malaria antigen. Infect Immun 66;2859-2865, 1998
  87. Fernandes I, Frisch B, Muller S, Schuber F: Synthetic lipopeptides incorporated in liposomes: in vitro stimulation of the proliferation of murine splenocytes and in vivo induction of an immune response against a peptide antigen. Mol Immunol 34;569-576, 1997 https://doi.org/10.1016/S0161-5890(97)00090-4
  88. Men Y, Gander B, Merkle HP, Corradin G: Induction of sustained and elevated immune responses to weakly immunogenic synthetic malarial peptides by encapsulation in biodegradable polymer microspheres. Vaccine 14;1442-1450, 1996 https://doi.org/10.1016/S0264-410X(96)00074-6
  89. Neuzil KM, Johnson JE, Tang YW, Prieels JP, Slaoui M, Gar N, Graham BS: Adjuvants influence the quantitative and qualitative immune response in BALB/c mice immunized with respiratory syncytial virus FG subunit vaccine. Vaccine 15;525-532, 1997 https://doi.org/10.1016/S0264-410X(97)00218-1
  90. Hunter RL, McNicholl J, Lal AA: Mechanisms of action of nonionic block copolymer adjuvants. AIDS Res Hum Retroviruses 10 Suppl 2;S95-S98, 1994
  91. Newman MJ, Todd CW, Lee EM, Balusubramanian M, Didier PJ, Katz JM: Increasing the immunogenicity of a trivalent influenza virus vaccine with adjuvant-active nonionic block copolymers for potential use in the elderly. Mech Ageing Dev 93;189-203, 1997 https://doi.org/10.1016/S0047-6374(96)01811-8
  92. Fast DJ, Vosika GJ: The muramyl dipeptide analog GMTPN-DPG preferentially induces cellular immunity to soluble antigens. Vaccine 15;1748-1752, 1997 https://doi.org/10.1016/S0264-410X(97)00110-2
  93. Bahr GM, Darcissac E, Bevec D, Dukor P, Chedid L: Immunopharmacological activities and clinical development of muramyl peptides with particular emphasis on murabutide. Int J Immunopharmacol 17;117-131, 1995 https://doi.org/10.1016/0192-0561(94)00094-5
  94. Payne LG, Jenkins SA, Woods AL, Grund EM, Geribo WE, Loebelenz JR, Andrianov AK, Roberts BE: Poly [di(carboxylatophenoxy)phosphazene] (PCPP) is a potent immunoadjuvant for an influenza vaccine [In Process Citation]. Vaccine 16;92-98, 1998 https://doi.org/10.1016/S0264-410X(97)00149-7
  95. Payne LG, Jenkins SA, Andrianov A, Roberts BE: Water- soluble phosphazene polymers for parenteral and mucosal vaccine delivery. Pharm Biotechnol 6;473-493, 1995
  96. Johnson AG: Molecular adjuvants and immunomodulators: New approaches to immunization. Clin Microbiol Rev 7;277-289, 1994 https://doi.org/10.1128/CMR.7.3.277
  97. Harrington DG, Crabbs CL, Hilmas DE, Brown JR, Hibbee GA, Cole FE Jr, Levy HB: Adjuvant effects of low doses of a nuclease resistant derivative of polyinosinic acid:polycytidylic acid on antibody responses of monkeys to inactivated Venezuelan equine encephalomyelitis virus vaccine. Infect Immun 24;160-166, 1978
  98. O'Hagan DT, MacKichan ML, Singh M: Recent developments in adjuvants for vaccines against infectious diseases. Biomolecular Engineering 18;69-85, 2001 https://doi.org/10.1016/S1389-0344(01)00101-0
  99. Singh M, O'Hagan DT: Recent advances in veterinary vaccine adjuvants. International J Parasitol 33;469-478, 2003 https://doi.org/10.1016/S0020-7519(03)00053-5